ABSTRACT
The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.
Subject(s)
Liver Diseases , Receptors, Steroid , Humans , Orphan Nuclear Receptors/metabolism , Receptors, Steroid/physiology , Ligands , Liver , Intercellular Signaling Peptides and ProteinsABSTRACT
Global warming is a serious environmental problem facing the world in the 21st century. Carbon dioxide, an important greenhouse gas, is the driver of global warming. Rapid urbanization has not only improved the quality of life, but has also led to radical increases in carbon emissions. In order to achieve a win-win situation between urbanization and carbon emissions reduction, research on the decoupling relationship between urbanization and carbon emissions has great significance, especially in Africa, where urbanization is advancing rapidly. This study explores the decoupling relationship between different types of urbanization (demographic urbanization, spatial urbanization, economic urbanization, social urbanization) and carbon emissions in Africa. The results show that the decoupling relationship between demographic urbanization and carbon emissions is similar to the decoupling relationship between spatial urbanization and carbon emissions. The decoupling relationship between economic urbanization and carbon emissions is similar to the decoupling relationship between social urbanization and carbon emissions. Only 4 of the 33 African countries studied have achieved the decoupling of four types of urbanization from carbon emissions in the long period (2000-2018). These findings can provide some guidance for the sustainable development of Africa.
ABSTRACT
Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.
Subject(s)
Collagen Type IV/metabolism , Down-Regulation/drug effects , Endothelial Cells/metabolism , Endothelin-1/metabolism , Hepatic Veins/drug effects , Laminin/metabolism , Naphthoquinones/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Animals , Basement Membrane/drug effects , Basement Membrane/metabolism , Capillaries/drug effects , Capillaries/metabolism , Hepatic Veins/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Liver/drug effects , Liver/metabolism , Liver Cirrhosis , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND/AIMS: Our previous studies have shown that plumbagin effectively inhibits hepatic stellate cell (HSC) proliferation. Thus, plumbagin-mediated anti-fibrotic effects in vivo merit further investigation. METHODS: We used rat models to assess the potential benefits of plumbagin against CCl4-induced liver fibrosis. RESULTS: The results showed that plumbagin lowered the serum concentrations of liver functional enzymes (ALT, AST, ALB, TBIL) in CCl4-fibrotic rats while reducing inflammatory cytokine levels (IL-6, TNF-α). As reflected in pathological examinations, rats that were administered plumbagin showed decreased collagen markers (HA, LN, PCIII and CIV) in liver tissues and improved hepatocellular impairments. In addition, plumbagin contributed to down-regulating NF-κB and TLR-4 mRNA in CCl4-lesioned livers. As revealed in the immunohistochemical assay, plumbagin-administered rats showed reduced levels of α-SMA and TNF-α immunoreactive cells in liver tissue. CONCLUSION: Collectively, these findings offer appealing evidence that plumbagin may serve as an anti-fibrotic medication through inactivating the NF-κB/TLR-4 pathway that is associated with inflammatory reactions, thereby mitigating liver fibrosis.
Subject(s)
Fibrinolytic Agents/pharmacology , Naphthoquinones/pharmacology , Actins/metabolism , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Body Weight/drug effects , Carbon Tetrachloride/toxicity , Collagen/metabolism , Down-Regulation/drug effects , Interleukin-6/metabolism , Liver/metabolism , Liver/pathology , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/pathology , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVE: To investigate the effect of plumbagin on the expression of TNF-alpha and PDGF-BB in human hepatic stellate cells (HSC-LX2) activated by Leptin. METHODS: HSC-LX2 were cultured in vitro and stimulated by Leptin for 24 hours then treated with different concentrations of plumbagin for 24 hours, the expressions of TNF-alpha mRNA and PDGF-BB mRNA were determined by Realtime quantitative PCR, the protein expressions of TNF-alpha and PDGF-BB were determined-by Western blotting. RESULTS: The expressions of TNF-alpha mRNA and PDGF-BB mRNA of treatment groups were significantly reduced, especially in high dose group (P < 0.01), and Western blotting analyses revealed similar trends in protein expression. CONCLUSION: Plumbagin may prevent the formation of hepatic fibrosis and its mechanism may be related to decreasing the level of mRNA of TNF-alpha and PDGF-BB and the protein of PDGF-BB.
